Dapagliflozin Drug Information

Generic name: DAPAGLIFLOZIN

Sodium-Glucose Cotransporter 2 Inhibitor [EPC]

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Uses of Dapagliflozin

  • Dapagliflozin tablets are indicated: To reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors. As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use Dapagliflozin tablets are not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. Dapagliflozin tablets are not recommended for use to improve glycemic control in patients with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m 2. Dapagliflozin tablets are likely to be ineffective in this setting based upon its mechanism of action. Pediatric use information is approved for AstraZeneca AB’s Farxiga ® (dapagliflozin) Tablets. However, due to AstraZeneca AB’s marketing exclusivity rights, this drug product is not labeled with that information. Dapagliflozin tablets is a sodium-glucose cotransporter 2 (SGLT2) inhibitor indicated: To reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors. As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
  • Limitations of use: Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. Not recommended for use to improve glycemic control in patients with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m 2. Dapagliflozin tablets are likely to be ineffective in this setting based upon its mechanism of action.

Dosage & Administration of Dapagliflozin

Testing

Prior to Initiation of Dapagliflozin Tablets Assess renal function prior to initiation of dapagliflozin tablets and then as clinically indicated . Assess volume status. In patients with volume depletion, correct this condition before initiating dapagliflozin tablets .

Recommended Dosage for Glycemic Control in Adults with Type 2 Diabetes Mellitus

In adults with type 2 diabetes mellitus, the recommended starting dosage of dapagliflozin tablets is 5 mg orally once daily to improve glycemic control. For additional glycemic control, the dosage can be increased to 10 mg orally once daily. For Adult Patients with Type 2 Diabetes Mellitus and Renal Impairment : The recommended dosage for dapagliflozin tablets in patients with an eGFR greater than or equal to 45 mL/min/1.73 m 2 is the same as the recommended dosage in patients with normal renal function.

Dapagliflozin tablets are not recommended for use to improve glycemic control in patients with type 2 diabetes mellitus with an eGFR less than 45 mL/min/1.73 m 2. Dapagliflozin tablets are likely to be ineffective to improve glycemic control in this setting based upon its mechanism of action. Pediatric use information is approved for AstraZeneca AB’s Farxiga ® (dapagliflozin) Tablets. However, due to AstraZeneca AB’s marketing exclusivity rights, this drug product is not labeled with that information.

Recommended Dosage for Other Indication in Adults

The recommended dosage of dapagliflozin tablets is 10 mg orally once daily in adults for the following indication: To reduce the risk of hHF in patients with type 2 diabetes mellitus and either established CV disease or multiple CV risk factors. For Adults with Renal Impairment Receiving Dapagliflozin Tablets for Indication Other than Glycemic Control: The recommended dosage of dapagliflozin tablets in patients with an eGFR greater than or equal to 25 mL/min/1.73 m 2 is the same as the recommended dosage in patients with normal renal function. Initiation with dapagliflozin tablets is not recommended in patients with an eGFR less than 25 mL/min/1.73 m 2.

Temporary Interruption for Surgery Withhold dapagliflozin tablets for at least 3 days

if possible, prior to major surgery or procedures associated with prolonged fasting. Resume dapagliflozin tablets when the patient is clinically stable and has resumed oral intake .

Side Effects of Dapagliflozin

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Dapagliflozin has been evaluated in clinical trials in adult patients with type 2 diabetes mellitus. The overall safety profile of dapagliflozin was consistent across the studied indications.

Severe hypoglycemia and diabetic ketoacidosis (DKA) were observed only in patients with diabetes mellitus. Clinical Trials for Glycemic Control in Adult Patients with Type 2 Diabetes Mellitus Pool of 12 Placebo-Controlled Adult Trials for Dapagliflozin 5 and 10 mg for Glycemic Control The data in Table 1 is derived from 12 glycemic control placebo-controlled trials in adult patients with type 2 diabetes mellitus ranging from 12 to 24 weeks. In 4 trials dapagliflozin was used as monotherapy, and in 8 trials dapagliflozin was used as add-on to background antidiabetic therapy or as combination therapy with metformin . These data reflect exposure of 2,338 adult patients to dapagliflozin with a mean exposure duration of 21 weeks.

Patients received placebo (N=1,393), dapagliflozin 5 mg (N=1,145), or dapagliflozin 10 mg (N=1,193) once daily. The mean age of the population was 55 years and 2% were older than 75 years of age. Fifty percent (50%) of the population were male; 81% were White, 14% were Asian, and 3% were Black or African American.

At baseline, the population had diabetes for an average of 6 years, had a mean hemoglobin A1c (HbA1c) of 8.3%, and 21% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired in 92% of patients and moderately impaired in 8% of patients (mean eGFR 86 mL/min/1.73 m 2 ). Table 1 shows common adverse reactions in adults associated with the use of dapagliflozin. These adverse reactions were not present at baseline, occurred more commonly on dapagliflozin than on placebo, and occurred in at least 2% of patients treated with either dapagliflozin 5 mg or dapagliflozin 10 mg.

Table 1: Adverse Reactions in Placebo-Controlled Trials of Glycemic Control Reported in ≥2% of Adults Treated with Dapagliflozin Adverse Reaction % of Patients Pool of 12 Placebo-Controlled Trials Placebo N=1,393 Dapagliflozin 5 mg N=1,145 Dapagliflozin 10 mg N=1,193 Female genital mycotic infections * 1.5 8.4

Nasopharyngitis 6.2 6.6 6.3 Urinary tract infections † 3.7 5.7 4.3 Back

pain 3.2 3.1

Increased urination ‡ 1.7 2.9 3.8 Male genital mycotic infections § 0.3

2.8

Nausea 2.4 2.8 2.5 Influenza 2.3 2.7 2.3 Dyslipidemia 1.5 2.1 2.5

Constipation 1.5 2.2

Discomfort with urination 0.7 1.6 2.1 Pain in extremity 1.4 2.0 1.7

* Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for females: vulvovaginal mycotic infection, vaginal infection, vulvovaginal candidiasis, vulvovaginitis, genital infection, genital candidiasis, fungal genital infection, vulvitis, genitourinary tract infection, vulval abscess, and vaginitis bacterial. (N for females: Placebo=677, dapagliflozin 5 mg=581, dapagliflozin 10 mg=598). † Urinary tract infections include the following adverse reactions, listed in order of frequency reported: urinary tract infection, cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis, urethritis, kidney infection, and prostatitis. ‡ Increased urination includes the following adverse reactions, listed in order of frequency reported: pollakiuria, polyuria, and urine output increased. § Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for males: balanitis, fungal genital infection, balanitis candida, genital candidiasis, genital infection male, penile infection, balanoposthitis, balanoposthitis infective, genital infection, and posthitis. (N for males: Placebo=716, dapagliflozin 5 mg=564, dapagliflozin 10 mg=595). Pool of 13 Placebo-Controlled Adult Trials for Dapagliflozin 10 mg for Glycemic Control Dapagliflozin 10 mg was also evaluated in a larger glycemic control placebo-controlled trial pool in adult patients with type 2 diabetes mellitus. This pool combined 13 placebo-controlled trials, including 3 monotherapy trials, 9 add-on to background antidiabetic therapy trials, and an initial combination with metformin trial. Across these 13 trials, 2,360 patients were treated once daily with dapagliflozin 10 mg for a mean duration of exposure of 22 weeks.

The mean age of the population was 59 years and 4% were older than 75 years. Fifty-eight percent (58%) of the population were male; 84% were White, 9% were Asian, and 3% were Black or African American. At baseline, the population had diabetes for an average of 9 years, had a mean HbA1c of 8.2%, and 30% had established microvascular disease.

Baseline renal function was normal or mildly impaired in 88% of patients and moderately impaired in 11% of patients (mean eGFR 82 mL/min/1.73 m 2 ). Other Adverse Reactions in Adult Patients with Type 2 Diabetes Mellitus Volume Depletion Dapagliflozin causes an osmotic diuresis, which may lead to a reduction in intravascular volume. Adverse reactions related to volume depletion (including reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension) in adult patients with type 2 diabetes mellitus for the 12-trial and 13-trial, short-term, placebo-controlled pools and for the DECLARE trial are shown in Table 2 . Table 2: Adverse Reactions Related to Volume Depletion* in Clinical Trials in Adults with Type 2 Diabetes Mellitus with Dapagliflozin Pool of 12 Placebo-Controlled Trials Pool of 13 Placebo- Controlled Trials DECLARE Trial Placebo Dapagliflozin 5 mg Dapagliflozin 10 mg Placebo Dapagliflozin 10 mg Placebo Dapagliflozin 10 mg Overall population N (%) N=1,393 5 (0.4%) N=1,145 7 (0.6%) N=1,193 9 (0.8%) N=2,295 17 (0.7%) N=2,360 27 (1.1%) N=8,569 207 (2.4%) N=8,574 213 (2.5%) Patient Subgroup n (%) Patients on loop diuretics n=55 1 (1.8%) n=40 0 n=31 3 (9.7%) n=267 4 (1.5%) n=236 6 (2.5%) n=934 57 (6.1%) n=866 57 (6.6%) Patients with moderate renal impairment with eGFR ≥30 and <60 mL/min/1.73 m 2 n=107 2 (1.9%) n=107 1 (0.9%) n=89 1 (1.1%) n=268 4 (1.5%) n=265 5 (1.9%) n=658 30 (4.6%) n=604 35 (5.8%) Patients ≥65 years of age n=276 1 (0.4%) n=216 1 (0.5%) n=204 3 (1.5%) n=711 6 (0.8%) n=665 11 (1.7%) n=3950 121 (3.1%) n=3948 117 (3.0%) * Volume depletion includes reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension. Hypoglycemia The frequency of hypoglycemia by trial in adult patients with type 2 diabetes mellitus is shown in Table 3. Hypoglycemia was more frequent when dapagliflozin was added to sulfonylurea or insulin . Table 3: Incidence of Severe Hypoglycemia* and Hypoglycemia with Glucose <54 mg/dL† in Controlled Glycemic Control Clinical Trials in Adults with Type 2 Diabetes Mellitus Placebo/Active Control Dapagliflozin 5 mg Dapagliflozin 10 mg Monotherapy (24 weeks) N=75 N=64 N=70 Severe 0 0 0 Glucose <54 mg/dL 0 0 0 Add-on to Metformin (24 weeks) N=137 N=137 N=135 Severe 0 0 0 Glucose <54 mg/dL 0 0 0 Add-on to Glimepiride (24 weeks) N=146 N=145 N=151 Severe 0 0 0 Glucose <54 mg/dL 1 3 5 Add-on to Metformin and a Sulfonylurea (24 Weeks) N=109 - N=109 Severe 0 - 0 Glucose <54 mg/dL 3 - 7 Add-on to Pioglitazone (24 weeks) N=139 N=141 N=140 Severe 0 0 0 Glucose <54 mg/dL 0 1 0 Add-on to DPP4 inhibitor (24 weeks) N=226 – N=225 Severe 0 – 1 Glucose <54 mg/dL 1 – 1 Add-on to Insulin with or without other OADs ‡ (24 weeks) N=197 N=212 N=196 Severe 1 2 2 Glucose <54 mg/dL 43 55 45 * Severe episodes of hypoglycemia were defined as episodes of severe impairment in consciousness or behavior, requiring external (third party) assistance, and with prompt recovery after intervention regardless of glucose level. † Episodes of hypoglycemia with glucose <54 mg/dL (3 mmol/L) were defined as reported episodes of hypoglycemia meeting the glucose criteria that did not also qualify as a severe episode. ‡ OAD = oral antidiabetic therapy.

In the DECLARE trial , severe events of hypoglycemia were reported in 58 (0.7%) out of 8574 adult patients treated with dapagliflozin and 83 (1.0%) out of 8569 adult patients treated with placebo. Genital Mycotic Infections In the glycemic control trials in adults, genital mycotic infections were more frequent with dapagliflozin treatment. Genital mycotic infections were reported in 0.9% of patients on placebo, 5.7% on dapagliflozin 5 mg, and 4.8% on dapagliflozin 10 mg, in the 12-trial placebo-controlled pool.

Discontinuation from trial due to genital infection occurred in 0% of placebo-treated patients and 0.2% of patients treated with dapagliflozin 10 mg. Infections were more frequently reported in females than in males (see Table 1). The most frequently reported genital mycotic infections were vulvovaginal mycotic infections in females and balanitis in males. Patients with a history of genital mycotic infections were more likely to have a genital mycotic infection during the trial than those with no prior history (10.0%, 23.1%, and 25.0% versus 0.8%, 5.9%, and 5.0% on placebo, dapagliflozin 5 mg, and dapagliflozin 10 mg, respectively). In the DECLARE trial , serious genital mycotic infections were reported in <0.1% of patients treated with dapagliflozin and <0.1% of patients treated with placebo.

Genital mycotic infections that caused trial drug discontinuation were reported in 0.9% of patients treated with dapagliflozin and <0.1% of patients treated with placebo. Hypersensitivity Reactions Hypersensitivity reactions (e.g., angioedema, urticaria, hypersensitivity) were reported with dapagliflozin treatment. In glycemic control trials in adults, serious anaphylactic reactions and severe cutaneous adverse reactions and angioedema were reported in 0.2% of comparator-treated patients and 0.3% of dapagliflozin-treated patients.

If hypersensitivity reactions occur, discontinue use of dapagliflozin; treat per standard of care and monitor until signs and symptoms resolve. Ketoacidosis in Patients with Diabetes Mellitus In the DECLARE trial , events of diabetic ketoacidosis (DKA) were reported in 27 out of 8574 adult patients in the dapagliflozin-treated group and 12 out of 8569 adult patients in the placebo group. The events were evenly distributed over the trial period.

Laboratory Tests in Adult Patients with Type 2 Diabetes Mellitus Increases in Serum Creatinine and Decreases in eGFR Initiation of SGLT2 inhibitors, including dapagliflozin causes a small increase in serum creatinine and decrease in eGFR. These changes in serum creatinine and eGFR generally occur within two weeks of starting therapy and then stabilize regardless of baseline kidney function. Changes that do not fit this pattern should prompt further evaluation to exclude the possibility of acute kidney injury . In two trials that included adult patients with type 2 diabetes mellitus with moderate renal impairment, the acute effect on eGFR reversed after treatment discontinuation, suggesting acute hemodynamic changes may play a role in the renal function changes observed with dapagliflozin. Increase in Hematocrit In the pool of 13 placebo-controlled trials of glycemic control, increases from baseline in mean hematocrit values were observed in dapagliflozin-treated adult patients starting at Week 1 and continuing up to Week 16, when the maximum mean difference from baseline was observed.

At Week 24, the mean changes from baseline in hematocrit were -0.33% in the placebo group and 2.30% in the dapagliflozin 10 mg group. By Week 24, hematocrit values >55% were reported in 0.4% of placebo-treated patients and 1.3% of dapagliflozin 10 mg-treated patients. Increase in Low-Density Lipoprotein Cholesterol In the pool of 13 placebo-controlled trials of glycemic control, changes from baseline in mean lipid values were reported in dapagliflozin-treated adult patients compared to placebo-treated patients.

Mean percent changes from baseline at Week 24 were 0.0% versus 2.5% for total cholesterol, and -1.0% versus 2.9% for LDL cholesterol in the placebo and dapagliflozin 10 mg groups, respectively. In the DECLARE trial , mean changes from baseline after 4 years were 0.4 mg/dL versus -4.1 mg/dL for total cholesterol, and -2.5 mg/dL versus -4.4 mg/dL for LDL cholesterol, in dapagliflozin-treated and the placebo groups, respectively. Decrease in Serum Bicarbonate In a trial of concomitant therapy of dapagliflozin 10 mg with exenatide extended-release (on a background of metformin) in adults, four patients (1.7%) on concomitant therapy had a serum bicarbonate value of less than or equal to 13 mEq/L compared to one each (0.4%) in the dapagliflozin and exenatide-extended release treatment groups . Pediatric use information is approved for AstraZeneca AB’s Farxiga ® (dapagliflozin) Tablets.

However, due to AstraZeneca AB’s marketing exclusivity rights, this drug product is not labeled with that information.

Postmarketing Experience Additional adverse reactions have been identified during post-approval use of

dapagliflozin in patients with diabetes mellitus. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Infections: Necrotizing fasciitis of the perineum (Fournier’s Gangrene), urosepsis and pyelonephritis Metabolism and Nutrition Disorders: Ketoacidosis Renal and Urinary Disorders: Acute kidney injury Skin and Subcutaneous Tissue Disorders: Rash

Warnings & Cautions for Dapagliflozin

Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis

In patients with type 1 diabetes mellitus, dapagliflozin significantly increases the risk of diabetic ketoacidosis, a life-threatening event, beyond the background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium-glucose cotransporter 2 (SGLT2) inhibitors compared to patients who received placebo. Dapagliflozin is not indicated for glycemic control in patients with type 1 diabetes mellitus.

Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors, including dapagliflozin. Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse.

Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing dapagliflozin ; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors.

Consider ketone monitoring in patients with type 1 diabetes mellitus and consider ketone monitoring in others at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue dapagliflozin, promptly evaluate, and treat ketoacidosis, if confirmed.

Monitor patients for resolution of ketoacidosis before restarting dapagliflozin. Withhold dapagliflozin, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume dapagliflozin when the patient is clinically stable and has resumed oral intake . Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue dapagliflozin and seek medical attention immediately if signs and symptoms occur.

Volume Depletion Dapagliflozin can cause intravascular volume depletion which may sometimes manifest

as symptomatic hypotension or acute transient changes in creatinine. There have been post-marketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors, including dapagliflozin. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m 2 ), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension.

Before initiating dapagliflozin in patients with one or more of these characteristics, assess volume status and renal function. Monitor for signs and symptoms of hypotension, and renal function after initiating therapy.

Urosepsis and Pyelonephritis Serious urinary tract infections including urosepsis and pyelonephritis requiring

hospitalization have been reported in patients receiving SGLT2 inhibitors, including dapagliflozin. Treatment with SGLT2 inhibitors increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated .

Hypoglycemia with

Concomitant Use with Insulin and Insulin Secretagogues Insulin and insulin secretagogues (e.g., sulfonylureas) are known to cause hypoglycemia. Dapagliflozin may increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue . Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when these agents are used in combination with dapagliflozin .

Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) Reports of necrotizing fasciitis of

the perineum (Fournier’s Gangrene), a rare but serious and life-threatening necrotizing infection requiring urgent surgical intervention, have been identified in postmarketing surveillance in patients with diabetes mellitus receiving SGLT2 inhibitors, including dapagliflozin. Cases have been reported in both females and males. Serious outcomes have included hospitalization, multiple surgeries, and death.

Patients treated with dapagliflozin presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise, should be assessed for necrotizing fasciitis. If suspected, start treatment immediately with broad-spectrum antibiotics and, if necessary, surgical debridement. Discontinue dapagliflozin, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

Genital Mycotic Infections Dapagliflozin increases the risk of genital mycotic infections. Patients

with a history of genital mycotic infections were more likely to develop genital mycotic infections . Monitor and treat appropriately.

Drug Interactions with Dapagliflozin

Table 4: Clinically Relevant Interactions with Dapagliflozin Insulin or Insulin Secretagogues Clinical Impact The risk of hypoglycemia may be increased when dapagliflozin is used concomitantly with insulin or insulin secretagogues (e.g., sulfonylurea) . Intervention Concomitant use may require lower doses of insulin or the insulin secretagogue to reduce the risk of hypoglycemia. Lithium Clinical Impact Concomitant use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations. Intervention Monitor serum lithium concentration more frequently during dapagliflozin initiation and dosage changes.

Positive Urine Glucose Test Clinical Impact SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Intervention Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control.

Interference with 1,5-anhydroglucitol (1,5-AG) Assay Clinical Impact Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Intervention Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control.

See full prescribing information for information on drug interactions and interference of dapagliflozin with laboratory tests.

Pregnancy Safety for Dapagliflozin

Pregnancy Risk Summary Based on animal data showing adverse renal effects, dapagliflozin is not recommended during the second and third trimesters of pregnancy. Limited data with dapagliflozin in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes and untreated heart failure in pregnancy (see Clinical Considerations). In animal studies, adverse renal pelvic and tubule dilatations, that were not fully reversible, were observed in rats when dapagliflozin was administered during a period of renal development corresponding to the late second and third trimesters of human pregnancy, at all doses tested; the lowest of which provided an exposure 15-times the 10 mg clinical dose (see Data). The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a HbA1c greater than 7% and has been reported to be as high as 20 to 25% in women with HbA1c greater than 10%. The estimated background risk of miscarriage for the indicated population is unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryofetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

Data Animal Data Dapagliflozin dosed directly to juvenile rats from postnatal day (PND) 21 until PND 90 at doses of 1, 15, or 75 mg/kg/day, increased kidney weights and increased the incidence of renal pelvic and tubular dilatations at all dose levels. Exposure at the lowest dose tested was 15-times the 10 mg clinical dose (based on AUC). The renal pelvic and tubular dilatations observed in juvenile animals did not fully reverse within a 1-month recovery period. In a prenatal and postnatal development study, dapagliflozin was administered to maternal rats from gestation day 6 through lactation day 21 at doses of 1, 15, or 75 mg/kg/day, and pups were indirectly exposed in utero and throughout lactation.

Increased incidence or severity of renal pelvic dilatation was observed in 21-day-old pups offspring of treated dams at 75 mg/kg/day (maternal and pup dapagliflozin exposures were 1415-times and 137-times, respectively, the human values at the 10 mg clinical dose, based on AUC). Dose-related reductions in pup body weights were observed at greater or equal to 29-times the 10 mg clinical dose (based on AUC). No adverse effects on developmental endpoints were noted at 1 mg/kg/day (19-times the 10 mg clinical dose, based on AUC). These outcomes occurred with drug exposure during periods of renal development in rats that corresponds to the late second and third trimester of human development. In embryofetal development studies in rats and rabbits, dapagliflozin was administered throughout organogenesis, corresponding to the first trimester of human pregnancy. In rats, dapagliflozin was neither embryolethal nor teratogenic at doses up to 75 mg/kg/day (1,441-times the 10 mg clinical dose, based on AUC). Dose-related effects on the rat fetus (structural abnormalities and reduced body weight) occurred only at higher dosages, equal to or greater than 150 mg/kg (more than 2,344-times the 10 mg clinical dose, based on AUC), which were associated with maternal toxicity.

No developmental toxicities were observed in rabbits at doses up to 180 mg/kg/day (1,191-times the 10 mg clinical dose, based on AUC).

Pediatric Use of Dapagliflozin

Pediatric Use The safety and effectiveness of dapagliflozin for glycemic control in type 2 diabetes mellitus have not been established in pediatric patients less than 10 years of age. The safety and effectiveness of dapagliflozin have not been established in pediatric patients to reduce the risk of : hospitalization for heart failure in patients with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors. Pediatric use information is approved for AstraZeneca AB’s Farxiga ® (dapagliflozin) Tablets.

However, due to AstraZeneca AB’s marketing exclusivity rights, this drug product is not labeled with that information.

Contraindications for Dapagliflozin

Dapagliflozin is contraindicated in patients with a history of a serious hypersensitivity reaction to dapagliflozin or any of the excipients in dapagliflozin. Serious hypersensitivity reactions, including anaphylaxis and angioedema have been reported with dapagliflozin . History of serious hypersensitivity reaction to dapagliflozin or any of the excipients in dapagliflozin.

Overdosage Information for Dapagliflozin

There were no reports of overdose during the clinical development program for dapagliflozin. In the event of an overdose, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. It is also reasonable to employ supportive measures as dictated by the patient’s clinical status.

The removal of dapagliflozin by hemodialysis has not been studied.

Clinical Studies of Dapagliflozin

Glycemic Control in Adults with Type 2 Diabetes Mellitus Overview of Clinical

Trials of Dapagliflozin in Adults with Type 2 Diabetes Mellitus Dapagliflozin has been studied in adult patients as monotherapy, in combination with metformin, pioglitazone, sulfonylurea (glimepiride), sitagliptin (with or without metformin), metformin plus a sulfonylurea, or insulin (with or without other oral antidiabetic therapy), compared to a sulfonylurea (glipizide), and in combination with a GLP-1 receptor agonist (exenatide extended-release) added-on to metformin. Dapagliflozin has also been studied in adult patients with type 2 diabetes mellitus and moderate renal impairment. Treatment with dapagliflozin as monotherapy and in combination with metformin, glimepiride, pioglitazone, sitagliptin, or insulin produced statistically significant improvements in mean change from baseline at Week 24 in HbA1c compared to control.

Reductions in HbA1c were seen across subgroups including gender, age, race, duration of disease, and baseline body mass index (BMI). Monotherapy A total of 840 treatment-naive adult patients with inadequately controlled type 2 diabetes mellitus participated in 2 placebo-controlled trials to evaluate the safety and efficacy of monotherapy with dapagliflozin. In one monotherapy trial, a total of 558 treatment-naive patients with inadequately controlled diabetes participated in a 24-week trial (NCT00528372). Following a 2-week diet and exercise placebo lead-in period, 485 patients with HbA1c ≥7% and ≤10% were randomized to dapagliflozin 5 mg or dapagliflozin 10 mg once daily in either the morning (QAM, main cohort) or evening (QPM), or placebo. At Week 24, treatment with dapagliflozin 10 mg QAM provided significant improvements in HbA1c and the fasting plasma glucose (FPG) compared with placebo (see Table 7). Table 7: Results at Week 24 (LOCF*) in a Placebo-Controlled Trial of Dapagliflozin Monotherapy in Adults with Type 2 Diabetes Mellitus (Main Cohort AM Doses) Efficacy Parameter Dapagliflozin 10 mg N=70 † Dapagliflozin 5 mg N=64 † Placebo N=75 † HbA1c (%) Baseline (mean) 8.0 7.8

Change from baseline (adjusted mean ‡ ) −0.9 −0.8 −0.2 Difference from

placebo (adjusted mean ‡ ) (95% CI) −0.7§ (−1.0, −0.4) −0.5 (−0.8, −0.2) Percent of patients achieving HbA1c <7% adjusted for baseline 50.8% ¶ 44.2% ¶ 31.6% FPG (mg/dL) Baseline (mean) 166.6 157.2

Change from baseline (adjusted mean ‡ ) −28.8 −24.1 −4.1 Difference from

placebo (adjusted mean ‡ ) (95% CI) −24.7§ (−35.7, −13.6) −19.9 (−31.3, −8.5) * LOCF: last observation (prior to rescue for rescued patients) carried forward. † All randomized patients who took at least one dose of double-blind trial medication during the short-term double-blind period. ‡ Least squares mean adjusted for baseline value. § p-value <0.0001 versus placebo. Sensitivity analyses yielded smaller estimates of treatment difference with placebo. ¶ Not evaluated for statistical significance as a result of the sequential testing procedure for the secondary endpoints. Initial Combination Therapy with Metformin XR A total of 1236 treatment-naive adult patients with inadequately controlled type 2 diabetes mellitus (HbA1c ≥7.5% and ≤12%) participated in 2 active-controlled trials of 24-week duration to evaluate initial therapy with dapagliflozin 5 mg or 10 mg in combination with metformin extended-release (XR) formulation.

In one trial (NCT00859898), 638 patients randomized to 1 of 3 treatment arms following a 1-week lead-in period received: Dapagliflozin 10 mg plus metformin XR (up to 2,000 mg per day), dapagliflozin 10 mg plus placebo, or metformin XR (up to 2,000 mg per day) plus placebo. Metformin XR dose was up-titrated weekly in 500 mg increments, as tolerated, with a median dose achieved of 2,000 mg. The combination treatment of dapagliflozin 10 mg plus metformin XR provided statistically significant improvements in HbA1c and FPG compared with either of the monotherapy treatments and statistically significant reduction in body weight compared with metformin XR alone (see Table 8 and Figure 2). Dapagliflozin 10 mg as monotherapy also provided statistically significant improvements in FPG and statistically significant reduction in body weight compared with metformin alone and was non-inferior to metformin XR monotherapy in lowering HbA1c.

Table 8: Results at Week 24 (LOCF*) in an Active-Controlled Trial of Dapagliflozin Initial Combination Therapy with Metformin XR Efficacy Parameter Dapagliflozin 10 mg + Metformin XR N=211 † Dapagliflozin 10 mg N=219 † Metformin XR N=208 † HbA1c (%) Baseline (mean) 9.1 9.0

Change from baseline (adjusted mean ‡ ) −2.0 −1.5 −1.4 Difference from

dapagliflozin (adjusted mean ‡ ) (95% CI) −0.5 § (−0.7, −0.3) Difference from metformin XR (adjusted mean ‡ ) (95% CI) −0.5 § (−0.8, −0.3) 0.0 ¶ (−0.2, 0.2) Percent of patients achieving HbA1c <7% adjusted for baseline 46.6%# 31.7% 35.2% FPG (mg/dL) Baseline (mean) 189.6 197.5

Change from baseline (adjusted mean ‡ ) −60.4 −46.4 −34.8 Difference from

dapagliflozin (adjusted mean ‡ ) (95% CI) −13.9 § (−20.9, −7.0) Difference from metformin XR (adjusted mean ‡ ) (95% CI) −25.5 § (−32.6, −18.5) −11.6 # (−18.6, −4.6) Body Weight (kg) Baseline (mean) 88.6 88.5

Change from baseline (adjusted mean ‡ ) −3.3 −2.7 −1.4 Difference from

metformin XR (adjusted mean ‡ ) (95% CI) −2.0 § (−2.6, −1.3) −1.4 § (−2.0, −0.7) *LOCF: last observation (prior to rescue for rescued patients) carried forward. † All randomized patients who took at least one dose of double-blind trial medication during the short-term double-blind period. ‡ Least squares mean adjusted for baseline value. § p-value <0.0001. ¶ Non-inferior versus metformin XR. # p-value <0.05. Figure 2: Adjusted Mean Change from Baseline Over Time in HbA1c (%) in a 24-Week Active- Controlled Trial of Dapagliflozin Initial Combination Therapy with Metformin XR In a second trial (NCT00643851), 603 patients were randomized to 1 of 3 treatment arms following a 1-week lead-in period: Dapagliflozin 5 mg plus metformin XR (up to 2,000 mg per day), dapagliflozin 5 mg plus placebo, or metformin XR (up to 2,000 mg per day) plus placebo. Metformin XR dose was up-titrated weekly in 500 mg increments, as tolerated, with a median dose achieved of 2,000 mg. The combination treatment of dapagliflozin 5 mg plus metformin XR provided statistically significant improvements in HbA1c and FPG compared with either of the monotherapy treatments and statistically significant reduction in body weight compared with metformin XR alone (see Table 9). Table 9: Results at Week 24 (LOCF*) in an Active-Controlled Trial of Dapagliflozin Initial Combination Therapy with Metformin XR Efficacy Parameter Dapagliflozin 5 mg + Metformin XR N=194 † Dapagliflozin 5 mg N=203 † Metformin XR N=201 † HbA1c (%) Baseline (mean) 9.2 9.1

Change from baseline (adjusted mean ‡ ) −2.1 −1.2 −1.4 Difference from

dapagliflozin (adjusted mean ‡ ) (95% CI) −0.9 § (−1.1, −0.6) Difference from metformin XR (adjusted mean ‡ ) (95% CI) −0.7 § (−0.9, −0.5) Percent of patients achieving HbA1c <7% adjusted for baseline 52.4% ¶ 22.5% 34.6% FPG (mg/dL) Baseline (mean) 193.4 190.8

Change from baseline (adjusted mean ‡ ) −61.0 −42.0 −33.6 Difference from

dapagliflozin (adjusted mean ‡ ) (95% CI) −19.1 § (−26.7, −11.4) Difference from metformin XR (adjusted mean ‡ ) (95% CI) −27.5§ (−35.1, −19.8) Body Weight (kg) Baseline (mean) 84.2 86.2

Change from baseline (adjusted mean ‡ ) −2.7 −2.6 −1.3 Difference from

metformin XR (adjusted mean ‡ ) (95% CI) −1.4 § (−2.0, −0.7) * LOCF: last observation (prior to rescue for rescued patients) carried forward. † All randomized patients who took at least one dose of double-blind trial medication during the short-term double-blind period. ‡ Least squares mean adjusted for baseline value. § p-value <0.0001. ¶ p-value <0.05. Add-On to Metformin A total of 546 adult patients with type 2 diabetes mellitus with inadequate glycemic control (HbA1c ≥7% and ≤10%) participated in a 24-week, placebo-controlled trial to evaluate dapagliflozin in combination with metformin (NCT00528879). Patients on metformin at a dose of at least 1,500 mg per day were randomized after completing a 2-week, single-blind, placebo lead-in period. Following the lead-in period, eligible patients were randomized to dapagliflozin 5 mg, dapagliflozin 10 mg, or placebo in addition to their current dose of metformin. As add-on treatment to metformin, dapagliflozin 10 mg provided statistically significant improvements in HbA1c and FPG, and statistically significant reduction in body weight compared with placebo at Week 24 (see Table 10 and Figure 3). Statistically significant (p <0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo plus metformin were −4.5 mmHg and −5.3 mmHg with dapagliflozin 5 mg and 10 mg plus metformin, respectively.

Table 10: Results of a 24-Week (LOCF*) Placebo-Controlled Trial of Dapagliflozin in Add-On Combination with Metformin Efficacy Parameter Dapagliflozin 10 mg + Metformin N=135 † Dapagliflozin 5 mg + Metformin N=137 † Placebo + Metformin N=137 † HbA1c (%) Baseline (mean) 7.9 8.2

Change from baseline (adjusted mean ‡ ) −0.8 −0.7 −0.3 Difference from

placebo (adjusted mean ‡ ) (95% CI) −0.5 § (−0.7, −0.3) −0.4 § (−0.6, −0.2) Percent of patients achieving HbA1c <7% adjusted for baseline 40.6% ¶ 37.5% ¶ 25.9% FPG (mg/dL) Baseline (mean) 156.0 169.2

Change from baseline at Week 24 (adjusted mean ‡ ) −23.5 −21.5

−

Difference from placebo (adjusted mean ‡ ) (95% CI) −17.5 § (−25.0

−10.0) −15.5 § (−22.9, −8.1) Change from baseline at Week 1 (adjusted mean ‡ ) −16.5 § (N=115) −12.0 § (N=121) 1.2 (N=126) Body Weight (kg) Baseline (mean) 86.3 84.7

Change from baseline (adjusted mean ‡ ) −2.9 −3.0 −0.9 Difference from

placebo (adjusted mean ‡ ) (95% CI) −2.0 § (−2.6, −1.3) −2.2 § (−2.8, −1.5) * LOCF: last observation (prior to rescue for rescued patients) carried forward. † All randomized patients who took at least one dose of double-blind trial medication during the short-term double-blind period. ‡ Least squares mean adjusted for baseline value. § p-value <0.0001 versus placebo + metformin. ¶ p-value <0.05 versus placebo + metformin. Figure 3: Adjusted Mean Change from Baseline Over Time in HbA1c (%) in a 24-Week Placebo- Controlled Trial of Dapagliflozin in Combination with Metformin Active Glipizide-Controlled Trial Add-On to Metformin A total of 816 adult patients with type 2 diabetes mellitus with inadequate glycemic control (HbA1c >6.5% and ≤10%) were randomized in a 52-week, glipizide-controlled, non-inferiority trial to evaluate dapagliflozin as add-on therapy to metformin (NCT00660907). Patients on metformin at a dose of at least 1,500 mg per day were randomized following a 2-week placebo lead-in period to glipizide or dapagliflozin (5 mg or 2.5 mg, respectively) and were up-titrated over 18 weeks to optimal glycemic effect (FPG <110 mg/dL, <6.1 mmol/L) or to the highest dose level (up to glipizide 20 mg and dapagliflozin 10 mg) as tolerated by patients. Thereafter, doses were kept constant, except for down-titration to prevent hypoglycemia.

At the end of the titration period, 87% of patients treated with dapagliflozin had been titrated to the maximum trial dose (10 mg) versus 73% treated with glipizide (20 mg). Dapagliflozin led to a similar mean reduction in HbA1c from baseline at Week 52 (LOCF), compared with glipizide, thus demonstrating non-inferiority (see Table 11). Dapagliflozin treatment led to a statistically significant mean reduction in body weight from baseline at Week 52 (LOCF) compared with a mean increase in body weight in the glipizide group. Statistically significant (p<0.0001) mean change from baseline in systolic blood pressure relative to glipizide plus metformin was -5.0 mmHg with dapagliflozin plus metformin. Table 11: Results at Week 52 (LOCF*) in an Active-Controlled Trial Comparing Dapagliflozin to Glipizide as Add-On to Metformin Efficacy Parameter Dapagliflozin + Metformin N=400 † Glipizide + Metformin N=401 † HbA1c (%) Baseline (mean) 7.7

Change from baseline (adjusted mean ‡ ) −0.5 −0.5 Difference from glipizide

+ metformin (adjusted mean ‡ ) (95% CI) 0.0 § (−0.1, 0.1) Body Weight (kg) Baseline (mean) 88.4

Change from baseline (adjusted mean ‡ ) −3.2 1.4 Difference from glipizide

+ metformin (adjusted mean ‡ ) (95% CI) −4.7 ¶ (−5.1, −4.2) * LOCF: last observation carried forward. † Randomized and treated patients with baseline and at least 1 post-baseline efficacy measurement. ‡ Least squares mean adjusted for baseline value. § Non-inferior to glipizide + metformin. ¶ p-value <0.0001. Add-On Combination Therapy with Other Antidiabetic Agents Add-On Combination Therapy with a Sulfonylurea A total of 597 adult patients with type 2 diabetes mellitus and inadequate glycemic control (HbA1c ≥7% and ≤10%) were randomized in this 24-week, placebo-controlled trial to evaluate dapagliflozin in combination with glimepiride (a sulfonylurea) (NCT00680745). Patients on at least half the maximum recommended dose of glimepiride as monotherapy (4 mg) for at least 8 weeks lead-in were randomized to dapagliflozin 5 mg, dapagliflozin 10 mg, or placebo in addition to glimepiride 4 mg per day. Down-titration of glimepiride to 2 mg or 0 mg was allowed for hypoglycemia during the treatment period; no up-titration of glimepiride was allowed. In combination with glimepiride, dapagliflozin 10 mg provided statistically significant improvement in HbA1c, FPG, and 2-hour PPG, and statistically significant reduction in body weight compared with placebo plus glimepiride at Week 24 (see Table 12). Statistically significant (p<0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo plus glimepiride were −2.8 mmHg and −3.8 mmHg with dapagliflozin 5 mg and 10 mg plus glimepiride, respectively.

Add-on Combination Therapy with Metformin and a Sulfonylurea A total of 218 adult patients with type 2 diabetes mellitus and inadequate glycemic control (HbA1c ≥7% and ≤10.5%) participated in a 24-week, placebo-controlled trial to evaluate dapagliflozin in combination with metformin and a sulfonylurea (NCT01392677). Patients on a stable dose of metformin (immediate- or extended-release formulations) ≥1,500 mg/day plus maximum tolerated dose, which must be at least half the maximum dose, of a sulfonylurea for at least 8 weeks prior to enrollment were randomized after an 8-week placebo lead-in period to dapagliflozin 10 mg or placebo. Dose-titration of dapagliflozin or metformin was not permitted during the 24–week treatment period. Down-titration of the sulfonylurea was permitted to prevent hypoglycemia, but no up-titration was permitted.

As add-on treatment to combined metformin and a sulfonylurea, treatment with dapagliflozin 10 mg provided statistically significant improvements in HbA1c and FPG and statistically significant reduction in body weight compared with placebo at Week 24 (Table 12). A statistically significant (p <0.05) mean change from baseline in systolic blood pressure relative to placebo in combination with metformin and a sulfonylurea was -3.8 mmHg with dapagliflozin 10 mg in combination with metformin and a sulfonylurea at Week 8. Add-On Combination Therapy with a Thiazolidinedione A total of 420 adult patients with type 2 diabetes mellitus with inadequate glycemic control (HbA1c ≥7% and ≤10.5%) participated in a 24-week, placebo-controlled trial to evaluate dapagliflozin in combination with pioglitazone alone (NCT00683878). Patients on a stable dose of pioglitazone of 45 mg per day (or 30 mg per day, if 45 mg per day was not tolerated) for 12 weeks were randomized after a 2-week lead-in period to 5 or 10 mg of dapagliflozin or placebo in addition to their current dose of pioglitazone. Dose titration of dapagliflozin or pioglitazone was not permitted during the trial. In combination with pioglitazone, treatment with dapagliflozin 10 mg provided statistically significant improvements in HbA1c, 2-hour PPG, FPG, the proportion of patients achieving HbA1c <7%, and a statistically significant reduction in body weight compared with the placebo plus pioglitazone treatment groups (see Table 12) at Week 24. A statistically significant (p <0.05) mean change from baseline in systolic blood pressure relative to placebo in combination with pioglitazone was −4.5 mmHg with dapagliflozin 10 mg in combination with pioglitazone.

Add-On Combination Therapy with a DPP4 Inhibitor A total of 452 adult patients with type 2 diabetes mellitus who were drug naive, or who were treated at entry with metformin or a DPP4 inhibitor alone or in combination, and had inadequate glycemic control (HbA1c ≥7.0% and ≤10.0% at randomization), participated in a 24-week, placebo-controlled trial to evaluate dapagliflozin in combination with sitagliptin (a DPP4 inhibitor) with or without metformin (NCT00984867). Eligible patients were stratified based on the presence or absence of background metformin (≥1,500 mg per day), and within each stratum were randomized to either dapagliflozin 10 mg plus sitagliptin 100 mg once daily, or placebo plus sitagliptin 100 mg once daily. Endpoints were tested for dapagliflozin 10 mg versus placebo for the total trial group (sitagliptin with and without metformin) and for each stratum (sitagliptin alone or sitagliptin with metformin). Thirty-seven percent (37%) of patients were drug naive, 32% were on metformin alone, 13% were on a DPP4 inhibitor alone, and 18% were on a DPP4 inhibitor plus metformin. Dose titration of dapagliflozin, sitagliptin, or metformin was not permitted during the trial.

In combination with sitagliptin (with or without metformin), dapagliflozin 10 mg provided statistically significant improvements in HbA1c, FPG, and a statistically significant reduction in body weight compared with the placebo plus sitagliptin (with or without metformin) group at Week 24 (see Table 12). These improvements were also seen in the stratum of patients who received dapagliflozin 10 mg plus sitagliptin alone (placebo-corrected mean change for HbA1c −0.56%; n=110) compared with placebo plus sitagliptin alone (n=111), and the stratum of patients who received dapagliflozin 10 mg plus sitagliptin and metformin (placebo-corrected mean change for HbA1c −0.40; n=113) compared with placebo plus sitagliptin with metformin (n=113). Add-On Combination Therapy with Insulin A total of 808 adult patients with type 2 diabetes mellitus who had inadequate glycemic control (HbA1c ≥7.5% and ≤10.5%) were randomized in a 24-week, placebo-controlled trial to evaluate dapagliflozin as add-on therapy to insulin (NCT00673231). Patients on a stable insulin regimen, with a mean dose of at least 30 IU of injectable insulin per day, for a period of at least 8 weeks prior to enrollment and on a maximum of 2 oral antidiabetic medications (OADs), including metformin, were randomized after completing a 2-week enrollment period to receive either dapagliflozin 5 mg, dapagliflozin 10 mg, or placebo in addition to their current dose of insulin and other OADs, if applicable. Patients were stratified according to the presence or absence of background OADs. Up- or down-titration of insulin was only permitted during the treatment phase in patients who failed to meet specific glycemic goals.

Dose modifications of blinded trial medication or OAD(s) were not allowed during the treatment phase, with the exception of decreasing OAD(s) where there were concerns over hypoglycemia after cessation of insulin therapy. In this trial, 50% of patients were on insulin monotherapy at baseline, while 50% were on 1 or 2 OADs in addition to insulin. At Week 24, dapagliflozin 10 mg dose provided statistically significant improvement in HbA1c and reduction in mean insulin dose, and a statistically significant reduction in body weight compared with placebo in combination with insulin, with or without up to 2 OADs (see Table 12); the effect of dapagliflozin on HbA1c was similar in patients treated with insulin alone and patients treated with insulin plus OAD. Statistically significant (p<0.05) mean change from baseline in systolic blood pressure relative to placebo in combination with insulin was −3.0 mmHg with dapagliflozin 10 mg in combination with insulin.

At Week 24, dapagliflozin 5 mg (−

IU, difference from placebo) and 10 mg (−6.2 IU, difference from placebo)

once daily resulted in a statistically significant reduction in mean daily insulin dose (p<0.0001 for both doses) compared to placebo in combination with insulin, and a statistically significantly higher proportion of patients on dapagliflozin 10 mg (19.6%) reduced their insulin dose by at least 10% compared to placebo (11.0%). Table 12: Results of 24-Week (LOCF*) Placebo-Controlled Trials of Dapagliflozin in Combination with Antidiabetic Agents Efficacy Parameter Dapagliflozin 10 mg Dapagliflozin 5 mg Placebo In Combination with Sulfonylurea (Glimepiride) Intent-to-Treat Population N=151 † N=142 † N=145 † HbA1c (%) Baseline (mean) 8.1 8.1

Change from baseline (adjusted mean ‡ ) −0.8 −0.6 −0.1 Difference from

placebo (adjusted mean ‡ ) (95% CI) −0.7 § (−0.9, −0.5) −0.5 § (−0.7, −0.3) Percent of patients achieving HbA1c <7% adjusted for baseline 31.7% § 30.3% § 13.0% FPG (mg/dL) Baseline (mean) 172.4 174.5

Change from baseline (adjusted mean ‡ ) −28.5 −21.2 −2.0 Difference from

placebo (adjusted mean ‡ ) (95% CI) −26.5 § (−33.5, −19.5) −19.3 § (−26.3, −12.2) 2-hour PPG¶ (mg/dL) Baseline (mean) 329.6 322.8

Change from baseline (adjusted mean ‡ ) −60.6 –54.5 −11.5 Difference from

placebo (adjusted mean ‡ ) (95% CI) −49.1 § (−64.1, −34.1) −43.0 § (–58.4, −27.5) Body Weight (kg) Baseline (mean) 80.6 81.0

Change from baseline (adjusted mean ‡ ) −2.3 −1.6 −0.7 Difference from

placebo (adjusted mean ‡ ) (95% CI) −1.5 § (−2.2, −0.9) −0.8§ (−1.5, −0.2) In Combination with Metformin and a Sulfonylurea Intent-to-Treat Population N=108 † - N=108 † HbA1c (%) Baseline (mean) 8.08 - 8.24 Change from baseline (adjusted mean ‡# ) −0.86 - −0.17 Difference from placebo (adjusted mean ‡# ) (95% CI) −0.69 § (−0.89, −0.49) - Percent of patients achieving HbA1c <7% adjusted for baseline 31.8% § - 11.1% FPG (mg/dL) Baseline (mean) 167.4 -

Change from baseline (adjusted mean ‡ ) −34.2 - −0.8 Difference from

placebo (adjusted mean ‡ ) (95% CI) −33.5 § (−43.1, −23.8) - Body Weight (kg) Baseline (mean) 88.57 - 90.07 Change from baseline (adjusted mean ‡ ) −2.65 - −0.58 Difference from placebo (adjusted mean ‡ ) (95% CI) −2.07 § (−2.79, −1.35) - In Combination with Thiazolidinedione (Pioglitazone) Intent-to-Treat Population N=140 Þ N=141 Þ N=139 Þ HbA1c (%) Baseline (mean) 8.4 8.4

Change from baseline (adjusted mean ‡ ) −1.0 −0.8 −0.4 Difference from

placebo (adjusted mean ‡ ) (95% CI) −0.6 § (−0.8, −0.3) −0.4 § (−0.6, −0.2) Percent of patients achieving HbA1c <7% adjusted for baseline 38.8% ß 32.5% ß 22.4% FPG (mg/dL) Baseline (mean) 164.9 168.3

Change from baseline (adjusted mean ‡ ) −29.6 −24.9 −5.5 Difference from

placebo (adjusted mean ‡ ) (95% CI) −24.1 § (−32.2, −16.1) −19.5 § (−27.5, −11.4) 2-hour PPG ¶ (mg/dL) Baseline (mean) 308.0 284.8

Change from baseline (adjusted mean ‡ ) −67.5 −65.1 −14.1 Difference from

placebo (adjusted mean ‡ ) (95% CI) −53.3 § (−71.1, −35.6) −51.0 § (−68.7, −33.2) Body Weight (kg) Baseline (mean) 84.8 87.8

Change from baseline (adjusted mean ‡ ) −0.1 0.1 1.6 Difference from

placebo (adjusted mean ‡ ) (95% CI) −1.8 § (−2.6, −1.0) −1.6 § (−2.3, −0.8) In Combination with DPP4 Inhibitor (Sitagliptin) with or without Metformin Intent-to-Treat Population N=223 † – N=224 † HbA1c (%) Baseline (mean) 7.90 – 7.97 Change from baseline (adjusted mean ‡ ) −0.45 – 0.04 Difference from placebo (adjusted mean ‡ ) (95% CI) −0.48 § (−0.62, −0.34) – Patients with HbA1c decrease ≥0.7% (adjusted percent) 35.4% – 16.6% FPG (mg/dL) Baseline (mean) 161.7 –

Difference from placebo (adjusted mean ‡ ) (95% CI) −27.9 § (−34.5

−21.4) – Body Weight (kg) Baseline (mean) 91.02 – 89.23 Change from baseline (adjusted mean ‡ ) −2.14 – −0.26 Difference from placebo (adjusted mean ‡ ) (95% CI) −1.89 § (−2.37, −1.40) – In Combination with Insulin with or without up to 2 Oral Antidiabetic Therapies Intent-to-Treat Population N=194 † N=211 † N=193 † HbA1c (%) Baseline (mean) 8.6 8.6

Change from baseline (adjusted mean ‡ ) −0.9 −0.8 −0.3 Difference from

placebo (adjusted mean ‡ ) (95% CI) −0.6 § (−0.7, −0.5) −0.5 § (−0.7, −0.4) FPG (mg/dL) Baseline (mean)

NT à 170.0 Change from baseline (adjusted mean ‡ ) −21.7 NT

à

Difference from placebo (adjusted mean ‡ ) (95% CI) −25.0 § (−34.3

−15.8) NT à Body Weight (kg) Baseline (mean) 94.6 93.2

Change from baseline (adjusted mean ‡ ) −1.7 −1.0 0.0 Difference from

placebo (adjusted mean ‡ ) (95% CI) −1.7 § (−2.2, −1.2) −1.0 § (−1.5, −0.5) * LOCF: last observation (prior to rescue for rescued patients) carried forward. † Randomized and treated patients with baseline and at least 1 post-baseline efficacy measurement. ‡ Least squares mean adjusted for baseline value based on an ANCOVA model. § p-value <0.0001 versus placebo. ¶ 2-hour PPG level as a response to a 75-gram oral glucose tolerance test (OGTT). # Least squares mean adjusted for baseline value based on a longitudinal repeated measures model. Þ All randomized patients who took at least one dose of double-blind trial medication during the short-term, double-blind period. ß p-value <0.05 versus placebo. à NT: Not formally tested because of failing to achieve a statistically significant difference in an endpoint that was earlier in the testing sequence. Combination Therapy with Exenatide-Extended Release as Add-On to Metformin A total of 694 adult patients with type 2 diabetes mellitus and inadequate glycemic control (HbA1c ≥8.0 and ≤12.0%) on metformin, were evaluated in a 28-week double-blind, active-controlled trial to compare dapagliflozin in combination with exenatide extended-release (a GLP-1 receptor agonist) to dapagliflozin alone and exenatide extended-release alone, as add-on to metformin (NCT02229396). Patients on metformin at a dose of at least 1,500 mg per day were randomized following a 1-week placebo lead-in period to receive either dapagliflozin 10 mg once daily (QD) in combination with exenatide extended-release 2 mg once weekly (QW), dapagliflozin 10 mg QD, or exenatide extended-release 2 mg QW. At Week 28, dapagliflozin in combination with exenatide extended-release provided statistically significantly greater reductions in HbA1c (-1.77%) compared to dapagliflozin alone (-1.32%, p=0.001) and exenatide extended-release alone (-1.42%, p=0.012). Dapagliflozin in combination with exenatide extended-release provided statistically significantly greater reductions in FPG (-57.35 mg/dL) compared to dapagliflozin alone (-44.72 mg/dL, p=0.006) and exenatide extended-release alone (-40.53, p <0.001). Use in Adults with Type 2 Diabetes Mellitus and Moderate Renal Impairment Dapagliflozin was assessed in two placebo-controlled trials of adult patients with type 2 diabetes mellitus and moderate renal impairment. Patients with type 2 diabetes mellitus and an eGFR between 45 to less than 60 mL/min/1.73 m 2 inadequately controlled on current diabetes therapy participated in a 24-week, double-blind, placebo-controlled clinical trial (NCT02413398). Patients were randomized to either dapagliflozin 10 mg or placebo, administered orally once daily.

At Week 24, dapagliflozin provided statistically significant reductions in HbA1c compared with placebo (Table 13). Table 13: Results at Week 24 of Placebo-Controlled Trial for Dapagliflozin in Adults with Type 2 Diabetes Mellitus and Renal Impairment (eGFR 45 to less than 60 mL/min/1.73 m2) Dapagliflozin 10 mg Placebo Number of patients: N=160 N=161 HbA1c (%) Baseline (mean) 8.3

Change from baseline (adjusted mean * ) -0.4 -0.1 Difference from placebo

(adjusted mean * ) (95% CI) -0.3 † (-0.5, -0.1) * Least squares mean adjusted for baseline value; at Week 24, HbA1c was missing for 5.6% and 6.8% of individuals treated with dapagliflozin and placebo, respectively. Retrieved dropouts, i.e., observed HbA1c at Week 24 from subjects who discontinued treatment, were used to impute missing values in HbA1c. † p-value =0.008 versus placebo. Pediatric use information is approved for AstraZeneca AB’s Farxiga ® (dapagliflozin) Tablets.

However, due to AstraZeneca AB’s marketing exclusivity rights, this drug product is not labeled with that information. 2 3

Cardiovascular Outcomes in Adults with Type 2 Diabetes Mellitus Dapagliflozin Effect on

Cardiovascular Events (DECLARE, NCT01730534) was an international, multicenter, randomized, double-blind, placebo-controlled, clinical trial conducted to determine the effect of dapagliflozin relative to placebo on cardiovascular (CV) outcomes when added to current background therapy. All patients had type 2 diabetes mellitus and either established CV disease or two or more additional CV risk factors (age ≥55 years in men or ≥60 years in women and one or more of dyslipidemia, hypertension, or current tobacco use). Concomitant antidiabetic and atherosclerotic therapies could be adjusted, at the discretion of investigators, to ensure participants were treated according to the standard care for these diseases. Of 17,160 randomized patients, 6,974 (40.6%) had established CV disease and 10,186 (59.4%) did not have established CV disease.

A total of 8,582 patients were randomized to dapagliflozin 10 mg, 8,578 to placebo, and patients were followed for a median of 4.2 years. Approximately 80% of the trial population was White, 4% Black or African American, and 13% Asian. The mean age was 64 years, and approximately 63% were male.

Mean duration of diabetes was 11.9 years and 22.4% of patients had diabetes for less than 5 years. Mean eGFR was 85.2 mL/min/1.73 m 2. At baseline, 23.5% of patients had microalbuminuria (UACR ≥30 to ≤300 mg/g) and 6.8% had macroalbuminuria (UACR >300 mg/g). Mean HbA1c was 8.3% and mean BMI was 32.1 kg/m 2. At baseline, 10% of patients had a history of heart failure. Most patients (98.1%) used one or more antihyperglycemic medications at baseline. 82.0% of the patients were being treated with metformin, 40.9% with insulin, 42.7% with a sulfonylurea, 16.8% with a DPP4 inhibitor, and 4.4% with a GLP-1 receptor agonist.

Approximately 81.3% of patients were treated with angiotensin converting enzyme inhibitors or angiotensin receptor blockers, 75.0% with statins, 61.1% with antiplatelet therapy, 55.5% with acetylsalicylic acid, 52.6% with beta-blockers, 34.9% with calcium channel blockers, 22.0% with thiazide diuretics, and 10.5% with loop diuretics. A Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio (HR) of the composite of CV death, myocardial infarction (MI), or ischemic stroke (MACE) and if non-inferiority was demonstrated, to test for superiority on the two primary endpoints: 1) the composite of hospitalization for heart failure or CV death, and 2) MACE. The incidence rate of MACE was similar in both treatment arms: 2.30 MACE events per 100 patient-years on dapagliflozin vs 2.46 MACE events per 100 patient-years on placebo. The estimated hazard ratio of MACE associated with dapagliflozin relative to placebo was 0.93 with a 95% CI of.

The upper bound of this confidence interval, 1.03, excluded the pre-specified non-inferiority margin of 1.3. Dapagliflozin was superior to placebo in reducing the incidence of the primary composite endpoint of hospitalization for heart failure or CV death. The treatment effect was due to a significant reduction in the risk of hospitalization for heart failure in subjects randomized to dapagliflozin, with no change in the risk of CV death (Table 15 and Figures 4 and 5). Table 15: Treatment Effects for the Primary Endpoints* and their Components* in the DECLARE Trial Patients with events n (%) Efficacy Variable (time to first occurrence) Dapagliflozin 10 mg N=8,582 Placebo N=8,578 Hazard ratio (95% CI) Primary Endpoints Composite of Hospitalization for Heart Failure, CV Death † 417 496 0.83 Composite Endpoint of CV Death, MI, Ischemic Stroke 756 803 0.93 Components of the composite endpoints ‡ Hospitalization for Heart Failure 212 286 0.73 CV Death 245 249 0.98 Myocardial Infarction 393 441 0.89 Ischemic Stroke 235 231 1.01 N=Number of patients, CI=Confidence interval, CV=Cardiovascular, MI=Myocardial infarction. * Full analysis set. † p-value =0.005 versus placebo. ‡ Total number of events presented for each component of the composite endpoints. Figure 4: Time to First Occurrence of Hospitalization for Heart Failure or CV Death in the DECLARE Trial Figure 5: Time to First Occurrence of Hospitalization for Heart Failure in the DECLARE Trial 4 5

Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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